Cedrick D. Dotson

Modulation of taste sensitivity by GLP-1 signaling

In many sensory systems, stimulus sensitivity is dynamically modulated through mechanisms of peripheral adaptation, efferent input, or hormonal action. In this way, responses to sensory stimuli can be optimized in the context of both the environment and the physiological state of the animal. Although the gustatory system critically influences food preference, food intake and metabolic homeostasis, the mechanisms for modulating taste sensitivity are poorly understood. In this study, we report that glucagon‐like peptide‐1 (GLP‐1) signaling in taste buds modulates taste sensitivity in behaving mice. We find that GLP‐1 is produced in two distinct subsets of mammalian taste cells, while the GLP‐1 receptor is expressed on adjacent intragemmal afferent nerve fibers. GLP‐1 receptor knockout mice show dramatically reduced taste responses to sweeteners in behavioral assays, indicating that GLP‐1 signaling normally acts to maintain or enhance sweet taste sensitivity. A modest increase in citric acid taste sensitivity in these knockout mice suggests GLP‐1 signaling may modulate sour taste, as well. Together, these findings suggest a novel paracrine mechanism for the regulation of taste function.

Bitter taste receptors influence glucose homeostasis.

TAS1R- and TAS2R-type taste receptors are expressed in the gustatory system, where they detect sweet- and bitter-tasting stimuli, respectively. These receptors are also expressed in subsets of cells within the mammalian gastrointestinal tract, where they mediate nutrient assimilation and endocrine responses. For example, sweeteners stimulate taste receptors on the surface of gut enteroendocrine L cells to elicit an increase in intracellular Ca2+ and secretion of the incretin hormone glucagon-like peptide-1 (GLP-1), an important modulator of insulin biosynthesis and secretion. Because of the importance of taste receptors in the regulation of food intake and the alimentary responses to chemostimuli, we hypothesized that differences in taste receptor efficacy may impact glucose homeostasis. To address this issue, we initiated a candidate gene study within the Amish Family Diabetes Study and assessed the association of taste receptor variants with indicators of glucose dysregulation, including a diagnosis of type 2 diabetes mellitus and high levels of blood glucose and insulin during an oral glucose tolerance test. We report that a TAS2R haplotype is associated with altered glucose and insulin homeostasis. We also found that one SNP within this haplotype disrupts normal responses of a single receptor, TAS2R9, to its cognate ligands ofloxacin, procainamide and pirenzapine. Together, these findings suggest that a functionally compromised TAS2R receptor negatively impacts glucose homeostasis, providing an important link between alimentary chemosensation and metabolic disease.

Modulation of Taste Sensitivity by GLP-1 Signaling in Taste Buds

Modulation of sensory function can help animals adjust to a changing external and internal environment. Even so, mechanisms for modulating taste sensitivity are poorly understood. Using immunohistochemical, biochemical, and behavioral approaches, we found that the peptide hormone glucagon‐like peptide‐1 (GLP‐1) and its receptor (GLP‐1R) are expressed in mammalian taste buds. Furthermore, we found that GLP‐1 signaling plays an important role in the modulation of taste sensitivity: GLP‐1R knockout mice exhibit a dramatic reduction in sweet taste sensitivity as well as an enhanced sensitivity to umami‐tasting stimuli. Together, these findings suggest a novel paracrine mechanism for the hormonal modulation of taste function in mammals.

Transformation of postingestive glucose responses after deletion of sweet taste receptor subunits or gastric bypass surgery

The glucose-dependent secretion of the insulinotropic hormone glucagon-like peptide-1 (GLP-1) is a critical step in the regulation of glucose homeostasis. Two molecular mechanisms have separately been suggested as the primary mediator of intestinal glucose-stimulated GLP-1 secretion (GSGS): one is a metabotropic mechanism requiring the sweet taste receptor type 2 (T1R2) + type 3 (T1R3) while the second is a metabolic mechanism requiring ATP-sensitive K(+) (K(ATP)) channels. By quantifying sugar-stimulated hormone secretion in receptor knockout mice and in rats receiving Roux-en-Y gastric bypass (RYGB), we found that both of these mechanisms contribute to GSGS; however, the mechanisms exhibit different selectivity, regulation, and localization. T1R3(-/-) mice showed impaired glucose and insulin homeostasis during an oral glucose challenge as well as slowed insulin granule exocytosis from isolated pancreatic islets. Glucose, fructose, and sucralose evoked GLP-1 secretion from T1R3(+/+), but not T1R3(-/-), ileum explants; this secretion was not mimicked by the K(ATP) channel blocker glibenclamide. T1R2(-/-) mice showed normal glycemic control and partial small intestine GSGS, suggesting that T1R3 can mediate GSGS without T1R2. Robust GSGS that was K(ATP) channel-dependent and glucose-specific emerged in the large intestine of T1R3(-/-) mice and RYGB rats in association with elevated fecal carbohydrate throughout the distal gut. Our results demonstrate that the small and large intestines utilize distinct mechanisms for GSGS and suggest novel large intestine targets that could mimic the improved glycemic control seen after RYGB.

Glucagon signaling modulates sweet taste responsiveness

The gustatory system provides critical information about the quality and nutritional value of food before it is ingested. Thus, physiological mechanisms that modulate taste function in the context of nutritional needs or metabolic status could optimize ingestive decisions. We report that glucagon, which plays important roles in the maintenance of glucose homeostasis, enhances sweet taste responsiveness through local actions in the mouse gustatory epithelium. Using immunohistochemistry and confocal microscopy, we found that glucagon and its receptor (GlucR) are coexpressed in a subset of mouse taste receptor cells. Most of these cells also express the T1R3 taste receptor implicated in sweet and/or umami taste. Genetic or pharmacological disruption of glucagon signaling in behaving mice indicated a critical role for glucagon in the modulation of taste responsiveness. Scg5−/− mice, which lack mature glucagon, had significantly reduced responsiveness to sucrose as compared to wild‐type littermates in brief‐access taste tests. No significant differences were seen in responses to prototypical salty, sour, or bitter stimuli. Taste responsiveness to sucrose was similarly reduced upon acute and local disruption of glucagon signaling by the GlucR antagonist L‐168,049. Together, these data indicate a role for local glucagon signaling in the peripheral modulation of sweet taste responsiveness.—Elson, A.E.T., Dotson, C.D., Egan, J.M., Munger, S.D. Glucagon signaling modulates sweet taste responsiveness. FASEB J. 24, 3960–3969 (2010). www.fasebj.org

TAS2R bitter taste receptors regulate thyroid function

Dysregulation of thyroid hormones triiodothyronine and thyroxine (T3/T4) can impact metabolism, body composition, and development. Thus, it is critical to identify novel mechanisms that impact T3/T4 production. We found that type 2 taste receptors (TAS2Rs), which are activated by bitter‐tasting compounds such as those found in many foods and pharmaceuticals, negatively regulate thyroid‐stimulating hormone (TSH)‐dependent Ca2+ increases and TSH‐dependent iodide efflux in thyrocytes. Immunohistochemical Tas2r‐dependent reporter expression and real‐time PCR analyses reveal that human and mouse thyrocytes and the Nthy‐Ori 3‐1 human thyrocyte line express several TAS2Rs. Five different agonists for thyrocyte‐expressed TAS2Rs reduced TSH‐dependent Ca2+ release in Nthy‐Ori 3‐1 cells, but not basal Ca2+ levels, in a dose‐dependent manner. Ca2+ responses were unaffected by 6‐n‐propylthiouracil, consistent with the expression of an unresponsive variant of its cognate receptor, TAS2R38, in these cells. TAS2R agonists also inhibited basal and TSH‐dependent iodide efflux. Furthermore, a common TAS2R42 polymorphism is associated with increased serum T4 levels in a human cohort. Our findings indicate that TAS2Rs couple the detection of bitter‐tasting compounds to changes in thyrocyte function and T3/T4 production. Thus, TAS2Rs may mediate a protective response to overingestion of toxic materials and could serve as new druggable targets for therapeutic treatment of hypo‐ or hyperthyroidism.—Clark, A. A., Dotson, C. D., Elson, A. E. T., Voigt, A., Boehm, U., Meyerhof, W., Steinle, N. I., Munger, S. D., TAS2R bitter taste receptors regulate thyroid function. FASEB J. 29, 164–172 (2015). www.fasebj.org

The Receptor Basis of Sweet Taste in Mammals

The taste of sweeteners is hedonically pleasing, suggests high caloric value in food, and contributes to increased intake. In recent years, many of the molecular mechanisms underlying the detection of sweeteners have been elucidated. Of particular note is the identification of the sweet taste receptor, the heteromeric G-protein-coupled receptor T1R2:T1R3, which responds to a vast array of chemically diverse natural and artificial sweeteners. In this chapter, we discuss some of the mechanisms underlying the detection of sweeteners by mammals, with a particular focus on the function and role of the T1R2:T1R3 receptor in these processes.

Peptide regulators of peripheral taste function

The peripheral sensory organ of the gustatory system, the taste bud, contains a heterogeneous collection of sensory cells. These taste cells can differ in the stimuli to which they respond and the receptors and other signaling molecules they employ to transduce and encode those stimuli. This molecular diversity extends to the expression of a varied repertoire of bioactive peptides that appear to play important functional roles in signaling taste information between the taste cells and afferent sensory nerves and/or in processing sensory signals within the taste bud itself. Here, we review studies that examine the expression of bioactive peptides in the taste bud and the impact of those peptides on taste functions. Many of these peptides produced in taste buds are known to affect appetite, satiety or metabolism through their actions in the brain, pancreas and other organs, suggesting a functional link between the gustatory system and the neural and endocrine systems that regulate feeding and nutrient utilization.

Behavioral Discrimination between Sucrose and Other Natural Sweeteners in Mice: Implications for the Neural Coding of T1R Ligands

In taste bud cells, two different T1R heteromeric taste receptors mediate signal transduction of sugars (the canonical “sweet” taste receptor, T1R2 + T1R3) and l-amino acids (the T1R1 + T1R3 receptor). The T1R1 + T1R3 receptor is thought to mediate what is considered the fifth basic taste quality “umami.” However, a subset of l-amino acids is “sweet tasting” to humans and appears to possess a “sucrose-like” taste quality to nonhuman mammals. This suggests, to varying degrees, that all of these compounds activate a single neural channel that leads to the perception of sweetness. The experiments detailed here were designed to test the ability of mice to distinguish between sucrose and various others sugars and l-amino acids in operant taste discrimination tasks. Mice had at least some difficulty discriminating sucrose from l-serine, l-threonine, maltose, fructose, and glucose. For example, when concentration effects are taken into consideration, mice discriminated poorly, if at all, sucrose from glucose or fructose and, to a lesser extent maltose, suggesting that sugars generate a unitary perceptual quality. However, mice were able to reliably discriminate sucrose from l-serine and l-threonine. Data gathered using a conditioned taste aversion assay also suggest that, although qualitatively similar to the taste of sucrose, l-serine and l-threonine generate distinctive percepts. In conclusion, it appears that some signals from taste receptor proteins binding with sugars and some l-amino acids converge somewhere along the gustatory neuraxis. However, the results of these experiments also imply that sweet-tasting l-amino acids may possess qualitative taste characteristics that are distinguishable from the prototypical sweetener sucrose.

Variation in the Gene TAS2R13 is Associated with Differences in Alcohol Consumption in Patients with Head and Neck Cancer

Variation in responsiveness to bitter-tasting compounds has been associated with differences in alcohol consumption. One strong genetic determinant of variation in bitter taste sensitivity is alleles of the TAS2R gene family, which encode chemosensory receptors sensitive to a diverse array of natural and synthetic compounds. Members of the TAS2R family, when expressed in the gustatory system, function as bitter taste receptors. To better understand the relationship between TAS2R function and alcohol consumption, we asked if TAS2R variants are associated with measures of alcohol consumption in a head and neck cancer patient cohort. Factors associated with increased alcohol intake are of strong interest to those concerned with decreasing the incidence of cancers of oral and pharyngeal structures. We found a single nucleotide polymorphism (SNP) located within the TAS2R13 gene (rs1015443 [C1040T, Ser259Asn]), which showed a significant association with measures of alcohol consumption assessed via the Alcohol Use Disorders Identification Test (AUDIT). Analyses with other SNPs in close proximity to rs1015443 suggest that this locus is principally responsible for the association. Thus, our results provide additional support to the emerging hypothesis that genetic variation in bitter taste receptors can impact upon alcohol consumption.